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Acta Neurol Scand 2006: 113: 426–432 DOI: 10.1111/j.1600-0404.2006.00645.

x Copyright  Blackwell Munksgaard 2006


Sensitivity of transcranial Doppler for

confirming brain death: a prospective study
of 270 cases
de Freitas GR, André C. Sensitivity of transcranial Doppler for G. R. de Freitas, C. Andr
confirming brain death: a prospective study of 270 cases. Department of Neurology, Hospital Universitrio
Acta Neurol Scand 2006: 113: 426–432. Clementino Fraga Filho, Universidade Federal do Rio de
 Blackwell Munksgaard 2006. Janeiro, Rio de Janeiro, Brazil

Objective – The reported sensitivity of transcranial Doppler

ultrasonography (TCD) for confirming brain death (BD) ranges from
91% to 100%. We assessed the frequency and causes of false-negative
results in TCD examination in a series of patients with BD and in the
literature. Methods – We carried out a prospective TCD examination
of consecutive patients with the clinical diagnosis of BD. Results – In Key words: brain death; diagnosis; transcranial
204 (75.5%) of 270 patients, TCD showed a pattern compatible with Doppler; ultrasonography
BD. The causes of the false-negative results were persistent flow in the Gabriel R. de Freitas, Rua Mrio Pederneiras 55,
intracranial arteries in 47 (17.4%) patients and a lack of signal in 19 206-I, Rio de Janeiro, RJ, CEP 22261-060, Brazil
(7%). Absence of sympathomimetic drug use [odds ratio (OR) 5.4, Tel.: +55 21 2246 2793
95% confidence interval (CI) 1.8–16.0, P ¼ 0.003) and female gender Fax: +55 21 2246 2793
(OR 3.7, 95% CI 1.1–12.5, P ¼ 0.03) were associated with false- e-mail: gfreitas@ufrj.br
negative results. A review of 16 studies showed a sensitivity of 88% and Presented in part at the 8th Congress of the European
a specificity of 98% of TCD for confirming BD. Conclusions – The Society of Neurosonology and Cerebral Hemodynamics,
sensitivity of TCD for confirming BD may be lower than previously Alicante, Spain, May 9–11, 2003, and published in
reported, but is probably similar to that of other non-invasive abstract form [Cerebrovasc Dis 2003; 16(Suppl. 2):25].
methods. The specificity of TCD is close to 100%. Uniform criteria are
needed for the routine use of TCD as a confirmatory test for BD. Accepted for publication February 24, 2006

The diagnosis of brain death (BD) is clinical. While intracranial arteries; and (ii) persistence of flow in
there is general agreement on the prerequisites and the intracranial arteries.
clinical examination for the clinical confirmation of The aim of this study was to assess the frequency
BD (1, 2), there is no consensus on the need for and causes of false-negative results in TCD exam-
complementary tests to corroborate the clinical ination in our series of patients with the clinical
signs. The differences range from no requirement diagnosis of BD and in the literature. We also
for any technical tests to a requirement for one or examined patient characteristics which were asso-
more neurophysiological tests in some countries ciated with false-negative results.
(3). In several countries, confirmatory testing is
mandatory (4).
As it is a relatively fast, inexpensive and non- Methods
invasive test, transcranial Doppler ultrasonogra-
phy (TCD) is being increasingly used to confirm
BD. According to the report of the Therapeutics Between April 2000 and February 2004, we carried
and Technology Assessment Subcommittee of the out a prospective TCD examination of patients
American Academy of Neurology (AAN), the with the clinical diagnosis of BD hospitalized in the
sensitivity of TCD for diagnosis of BD ranges metropolitan region of Rio de Janeiro, Brazil. As
from 91% to 100% (5). confirmatory tests are not readily available in most
There are two causes of false-negative TCD hospitals in this region, clinically documented
results in BD patients: (i) a lack of signal in the cases of BD are reported to a central organ

Transcranial Doppler and brain death

transplantation organization, which provides TCD persistent flow group, as these findings could result
or electroencephalography (EEG) within a few from transmission problems, and possible intra-
hours after notification. The clinical diagnosis of cranial flow could not be excluded (7). Only the
BD is established according to Brazilian legislation first TCD examination after the clinical diagnosis
criteria, which are similar to those of the AAN (1). of BD was considered.
Briefly, in subjects older than 2 years, two neuro-
logical examinations, each including an apnoea
test, must be performed 6 h apart and at least one
must be performed by a neurologist or neurosur- The data were analysed using Intercooled Stata,
geon. version 6.0 (Stata Corporation, College Station,
The data recorded were age, gender, cause of TX, USA). We compared the characteristics of
BD, history of neurosurgery (including intracranial brain dead patients with or without the diagnosis
pressure monitoring), presence of skull fracture, of CCA by TCD using the Fisher’s exact, chi-
blood pressure, administration of sympathomimet- squared and Student’s t-tests. A two-sided P-value
ic drugs during TCD, and time between the initial less than 0.05 was considered statistically signifi-
clinical diagnosis of BD and TCD. cant. We also evaluated differences between sub-
The study protocol was approved by the Ethics groups of patients without CCA (persistence of
Committee of the Universidade Federal do Rio de flow and lack of signal) by univariate analysis.
Janeiro. Multivariate analysis was performed by stepwise
logistic regression including those factors shown to
be significant by univariate analysis. The results of
Transcranial Doppler
the logistic regression are presented using 95%
All TCD examinations were performed by the confidence intervals (CI).
same investigator (GRdF) using a 2 MHz pulsed
Doppler instrument (TC-22 Legend; SciMed, Bris-
Review of the literature
tol, UK). The middle cerebral arteries (MCA) were
insonated through the temporal window, the ver- We performed an electronic search of MEDLINE
tebral arteries and the basilar artery (VBA) using the following combination of medical subject
through the suboccipital window, and the internal heading (MeSH) terms: brain death [MeSH Major
carotid artery (ICA) siphons using the transorbital Topic] AND (ultrasonography [MeSH Major
approach. The filter was set at its lowest level. Topic] OR Ultrasonography, Doppler, Transcra-
The TCD criteria for the diagnosis of BD were nial [MeSH Major Topic]). We also systematically
adapted from those of the World Federation of explored the Ôrelated articlesÕ function of MED-
Neurology (WFN) (6): oscillating flow or short LINE for each relevant reference found. The
systolic spikes (shorter than 50 cm/s) had to be reference lists of relevant articles and published
demonstrated in at least two different arteries – the reviews were further scanned for additional rele-
VBA counting as one artery (e.g. VBA and one vant papers.
MCA, VBA and one ICA, both MCA, both ICA, We looked for studies that primarily addressed
or one ICA plus the contralateral MCA) – and no the use of TCD in patients with the clinical
signal could be detected in the remaining arteries; diagnosis of BD. We excluded (i) studies in which
absence of flow had to be present for at least it was not clearly stated whether TCD was
30 min; and patients with an arterial blood pres- performed before, or after, the clinical diagnosis
sure lower than 90 mmHg were excluded. A lack of of BD (8); (ii) studies with small samples (i.e.
signal was not considered proof of cerebral circu- arbitrarily set as less than 10 patients); (iii) case
latory arrest (CCA), as this finding can be caused reports, letters to the editor and reviews; and
by transmission problems. However, disappear- (iv) studies not published in English, French,
ance of intracranial flow (lack of signal in patients Portuguese or Spanish.
who had a detectable signal when not in BD) was The following variables were collected from each
accepted as proof of CCA. For the purposes of the selected study: (i) number of patients in BD and
present study, and in contrast to the WFN criteria, not in BD (control), (ii) cause of BD, (iii) test
persistence of isolated flow in the ICA with sensitivity and cause of false-negative results,
demonstration of CCA in all other intracranial (iv) criteria for patients being entered in the
arteries was considered compatible with CCA, as study, and, whenever possible, (v) specificity.
suggested previously (7). When there was persist- The sensitivity and specificity reported here do
ence of flow in the ICA, but no signal in the not necessarily correspond to the values reported
ipsilateral MCA, patients were included in the in the original papers. For example, we included

de Freitas & André

patients with a lack of signal in the group of characteristic of flow arrest in at least two intra-
false-negative results, which has not been done cranial arteries, thus confirming the diagnosis of
systematically by some authors (9, 10). Thus, the CCA.
sensitivity reported here for these studies may be In 19 (7%) brain dead patients without CCA, a
lower than that initially reported. On the other lack of signal was observed in TCD examination
hand, in some studies, some patients were consid- (in all intracranial arteries in four, in all intracra-
ered as false negatives because of an absence of a nial arteries except the VBA in eight, in the left
signal, but with a previous examination confirming ICA in three, and in the left MCA or the right ICA
an adequate temporal window (11, 12). We con- in two patients each). A lack of signal was
sidered these findings compatible with the diagno- positively associated with female gender and neg-
sis of CCA. Some of the values for specificity are atively associated with the presence of a skull
also different, as some authors did not consider as opening (Tables 1 and 2).
false positives patients with CCA and residual In 37 (13.7%) brain dead patients without CCA,
brain stem reflexes, who only later evolved to BD persistent flow (diastolic forward flow or systolic
(13). flow without a diastolic component) was observed
in the intracranial arteries. Forward flow was seen
in the left MCA in 20 patients, the right MCA in
19, the left ICA in 17, the right ICA in 16 and the
Two hundred and eighty brain dead patients were VBA in 16. Intracranial flow was observed in only
investigated using TCD. Ten were excluded one artery in eight patients, in two arteries in 13, in
because of low systolic blood pressure despite the three arteries in 12, in four arteries in three and in
administration of high doses of sympathomimetic all five arteries in one. Four of the patients with
drugs. The characteristics of the remaining 270 persistent intracranial flow in both MCAs had
patients are shown in Table 1. In 204 (75.5%) brain imaging results compatible with the diagnosis
patients, the first TCD examination gave a pattern of isolated brain stem death. There was an inverse

Table 1 Comparison of the characteristics of patients with and without CCA

Patients without CCA

Persistent intracranial flow

Patients with CCA Lack of signal Observed Possible

(n ¼ 204) (n ¼ 19) (n ¼ 37) (n ¼ 10) Total (n ¼ 66) P-value*

Age (mean, SD), years 39.2  18.5 44.5  17.5 35.9  18.7 41.1  16.0 39.2  18.1 0.9 
Male (%) 118 (58) 5 (26)§ 22 (59.5) 5 (50) 32 (48.5) 0.1
Ethnic group (%)
Caucasian 117 (57.5) 9 (47.5) 24 (65) 3 (30) 36 (54.5) 0.8
Afro-Brazilian 86 (42) 10 (52.5) 13 (35) 7 (70) 30 (44.5)
Asiatic 1 (0.5) 0 0 0 0
Cause of brain death 0.8à
TBI (%) 68 (33.5) 2 (10.5) 15 (40.5) 2 (20) 19 (29)
SAH (%) 65 (32) 6 (31.5) 9 (24.5) 1 (10) 16 (24)
ICH (%) 31 (15) 6 (31.5) 5 (13) 4 (40) 15 (22.5)
CI (%) 18 (9) 1 (5.5) 2 (5.5) 3 (30) 6 (9)
AE (%) 9 (4.5) 0 4 (11) 0 4 (6)
Others (%) 13 (6.5) 4 (21) 2 (5.5) 0 6 (9)
Skull opening (%)– 86 (42) 3 (15.5)§ 19 (51.5) 4 (40) 26 (40) 0.7
Systolic blood pressure (mean, SD), mmHg 109.2  27.5 102.2  21.4 105.5  25.7 121.5  31.5 107.1  25.9 0.6 
Hours elapsed between clinical diagnosis and TCD (%)**
£6 15 (8.5) 2 (13.5) 6 (16)§ 1 (11)§ 8 (14) 0.02à
>6 –12 79 (44) 5 (33.5) 15 (40.5) 1 (11) 21 (37)
>12–24 46 (25.5) 4 (26.5) 1 (2.5) 7 (78) 6 (10.5)
>24 39 (22) 4 (26.5) 11 (29.7) 22 (38.5)
Sympathomimetic drugs 176 (86.5) 3 (84) 25 (67.5)§ 9 (90) 50 (75.5) 0.03

CCA, cerebral circulatory arrest; SD, standard deviation; TBI, traumatic brain injury; SAH, subarachnoid haemorrhage; ICH, intracerebral haemorrhage; CI, cerebral infarction;
AE, anoxic encephalopathy; TCD, transcranial Doppler.
*Comparison of patients with and without CCA using Fisher's exact test, except where shown as  Student's t-test or àchi-squared test.
P £ 0.01 for a subgroup of patients without CCA compared with all other patients.

A history of neurosurgery (including intracranial pressure monitoring) or skull fracture.
**Data available for 179 patients with CCA and 57 patients without CCA.

Transcranial Doppler and brain death

Table 2 Comparison of the characteristics of patients with and without lack of signal

Patients with lack of signal (n ¼ 19) Patients without lack of signal (n ¼ 251)

Male Female Male Female

Gender (%)* 5 (26) 14 (74) 145 (58) 107 (42)

Age (mean, SD), years 52.2  13.9 39.3  18.9 35.8  19.8** 43.6  15.4**
Ethnic group (%)
Caucasian 2 (40) 7 (50) 89 (61.5) 57 (53)
Afro-Brazilian 3 (60) 7 (50) 55 (38) 50 (47)
Asiatic 1 (0.5)

*P ¼ 0.01 for comparison of patients with and without lack of signal using chi-squared test.
**P £ 0.01 for comparison of female and male patients without lack of signal. All other comparisons were non-significant.

association between the observed persistence of intracranial flow was the main cause of false-
intracranial flow and both the interval between the negative results, being twice as common as lack of
clinical diagnosis of BD and TCD examination and signal. The sensitivity found in this series is lower
sympathomimetic drug administration (Table 1). than the 91–100% reported by the AAN Subcom-
In 10 (3.7%) brain dead patients, there was mittee Assessment (5), but is in line with recent
possible persistence of intracranial flow (flow in the reports (10, 12, 28). The discrepancy can probably
ICA with no signal in the ipsilateral MCA). be explained by important methodological short-
When we considered all 66 patients with initial comings of most studies.
false-negative results, sympathomimetic drug use
and time between the clinical diagnosis of BD and
Persistence of flow
TCD examination were both associated with false-
negative results (Table 1). In the multivariate ana- Persistent flow in intracranial arteries was more
lysis including gender, skull opening, time from common in our series (17.4%) than in the review of
clinical diagnosis to TCD and sympathomimetic the literature (5%). One of the most important
drug use, only the absence of sympathomimetic shortcomings of many studies may have been the
drug use (OR 5.4, 95% CI 1.8–16.0, P ¼ 0.003) and selective inclusion of patients in whom the diag-
female gender (OR 3.7, 95% CI 1.1–12.5, P ¼ 0.03) nosis of BD was confirmed by other tests (e.g.
were associated with false-negative results. EEG, angiography) before TCD (9, 14, 25) (selec-
The results of the review of 16 studies are tion bias). As all confirmatory tests can show
presented in Table 3 (9–28). The overall sensitivity residual flow or electrical activity in the first hours
of TCD for confirming BD was 88% and the after BD, a biased sample of patients may have
causes of false-negative results were a lack of signal been evaluated, giving a low rate of false-negative
in 7% (47 of 680) of the patients and persistence of results and thus a high sensitivity. This hypothesis
flow in 5% (34 of 680). The overall specificity was is supported by our findings of an association
98%. All five patients with a false-positive result between the presentation of intracranial flow and
died: three had respiratory drive or cough reflexes, the interval between the clinical diagnosis of BD
but no other brain stem reflexes at the time of the and TCD examination. Moreover, a requirement
examination and evolved to BD (12, 13, 26), while for the use of sympathomimetic drugs may be a
the other two died of cardiopulmonary arrest more physiological marker of deterioration after
before the diagnosis of BD (21). The TCD criteria BD than the time after diagnosis. In fact, after
used to confirm BD were variable: only seven multivariate analysis, patients not receiving vaso-
groups examined the VBA (9, 10, 17), some active amines had a fivefold higher incidence of
authors accepted demonstration of absence of false-negative results than patients needing pres-
flow in only one artery (15, 21), and the definition sure support with vasoactive amines.
of forward flow was not uniform. It may be argued that arteriography is usually
considered the Ôgold standardÕ test for confirming
BD and that few cases of persistent flow are
reported. However, there is a clear correlation
In this, the largest series of consecutive patients between the level of CCA on angiography and the
with the clinical diagnosis of BD examined using TCD pattern (16, 18), and arteriography is
TCD, we found a sensitivity of TCD for confirm- usually performed long after the diagnosis of BD.
ing BD of 75.5%. The high rate of persistence of We agree with Plum that Ôthis long delay [in

Table 3 Studies addressing the role of TCD in assessing brain death

BD/control Arteries Sensitivity Causes of false Specificity False

Reference patients (n) Causes* examined  (%) negatives (%) positives (n) Characteristics
de Freitas & André

Ropper et al. (14) 24 10 SAH, 8 TBI, 5 IS, 1 AE MCA, ICA 91.6 2 PF – – Only patients with isoelectric EEG
(3 patients with IBSD were excluded)
Kirkham et al. (15) 13àà/6 8 AE, 3 TBI, 2 Ot MCA 92.3 1 PF 100 0
Van Velthoven et al. (17) 29 23 TBI, 4 ICH, 1 SAH MCA, ICA, VBA 89.6 3 LS – – Only candidates for organ donation
1 Ot
Powers et al. (21) 18/3 10 TBI, 3 SAH, 3 ICH, 2 AE MCA 94.5 1 PF 33.3 2
Newell et al. (19) 12 10 TBI, 2 ICH MCA 100 – – –
Petty et al. (9) 26/28 15 SAH, 15 IS, 7 ICH, 7 AE, 3 TBI, 5 Ot MCA, VBA 88.5 2 PF (1 probable IBSD) 100 0 Only patients with isoelectric EEG
1 LS
Zurynski et al. (11) 111/29 63 TBI, 39 SAH, 8 AE, 4 Ot MCA 93.7 3 PF (1 IBSD); 4 LS 100 0
Dvalos et al. (10) 16à/10 9 TBI, 3 EA, 1 ICH§ MCA, ICA, VBA– 75 1 PF 100 0
3 LS
Feri et al. (22) 22/15 12 ICH, 4 TBI, 3 AE, 1 SAH, 2 Ot MCA 86.3 3 LS 100 0 Only non-surgical patients
Paolin et al. (23) 15 6 TBI, 4 ICH, 4 SAH, 1 Ot MCA 53.3 1 PF
4 LS
Ducrocq et al. (25) 130 76 TBI, 27 SAH, 11 ICH, 16 Ot MCA, ICA 94.6 2 PF – – Only patients with isoelectric EEG
5 LS or no flow in arteriography
Hadani et al. (26) 84/53 48 TBI, 11 SAH, 10 ICH, 8 EA, 2 IS, 5 AE MCA, ICA, VBA 96.4 1 PF 98.1 1
2 LS
Azevedo et al. (27) 22/55 8 TBI, 5 ICH, 2 IS, 1 SAH, 6 Ot MCA, ICA, VBA 90.9 2 PF (probable IBSD) 100 – Retrospective

Nebra et al. (13) 25 13 TBI, 10 ICH, 2 SAH MCA, VBA 100 – 1

Lampl et al. (28) 57 NR MCA, ICA, VBA 87.7 7 LS –

Dosemeci et al. (12) 76/40 33 ICH, 32 TBI, 13 SAH, 8 IS, 6 AE, 8 Ot** MCA, ICA 56.6 18 PF 97.5 1
15 LS
Total 680/239 – 88.1 34 PF 98.3   5
47 LS

AE, anoxic encephalopathy; BD, brain death; EEG, electroencephalogram; IBSD, isolated brain stem death; ICA, internal carotid artery; ICH, intracranial haemorrhage; IS, ischaemic stroke; LS, lack of signal; MCA, middle cerebral artery; NR, not
reported; Ot, other; PF, persistence of flow; SAH, subarachnoid haemorrhage; TBI, traumatic brain injury; VBA, vertebral and basilar arteries
*Unless otherwise specified, refers only to the cause of BD, not the cause of the comatose state in controls.
Arteries systematically examined.
Nine patients received barbiturates.
Cause of BD in 13 patients with an adequate temporal window.

Examination of the ICA and VBA was performed when the temporal window was inadequate.
**The cause of coma in the 100 patients (BD and controls) with an adequate temporal window.
Four false-positive patients were included in the calculation, as there was no control group in the study of Nebra et al. (13).
Indicates brain stem death.
Transcranial Doppler and brain death

performing angiography] may explain why so few Ôlack of signalÕ. In our series, the rate of lack of
examples of continued blood flow have been signal was much lower than in other studies.
reported after BDÕ (29). We examined patients who were potential organ
donors. This group may be younger and have
different causes of BD (e.g. a higher proportion of
Lack of signal
traumatic brain injury) than patients in routine
On the contrary, the 7% incidence of a lack of signal practice. Although we did not observe differences
in our series is lower than that of 20% found by in flow characteristics between the diverse aetiol-
others (12), and no signal in all intracranial arteries ogies of BD, a lower frequency of skull opening
was seen in only 1.5% of the patients. However, this and a higher age (and thus inadequate temporal
value was similar to that found in our review of the window) may change the rate of false-negative tests
literature. The low incidence of a lack of signal in the in other populations.
present study may be explained by the use of In most patients with Ôlack of signalÕ it was
windows from natural foramina, namely the trans- probably caused by CCA rather than by transmis-
foraminal window for insonation of the VBA and sions problems, particularly when transforaminal
the transorbital window for insonation of the ICA, and transorbital approaches showed Ôno signalÕ.
and by the lowering of the filter setting. This value However, in some patients it may be difficult to
would be even smaller if, as in another study (13), we insonate the vertebral arteries, especially in intu-
had been able to show that absence of flow was due bated, uncooperative patients. Therefore, we prefer
to actual disappearance of flow, rather than to to adopt conservative criteria in these patients, in
transmission problems. Performing TCD examina- accordance with the WFN guidelines (6).
tions on all patients with severe head trauma and Finally, we accepted isolated flow in the ICA
stroke when they arrive in the emergency room with demonstration of CCA in all other arteries as
could give important diagnostic and prognostic compatible with BD. Although we and others have
information and, if they subsequently develop BD, clearly shown by using TCD (7, 26) and arteriog-
would make it possible to say which patients had a raphy (32–34) that BD patients may have flow in
loss of flow and which an inadequate temporal the ICA, many authors still refuse to accept any
window. It is well known that an increased thickness persistent flow as compatible with BD. Only
of the diploe of the temporal bone, and thus an prospective, multicentre confirmation of these
inadequate temporal window, is seen in females (30). findings would solve this issue.
Thus, it was not surprising to find that a lack of
signal was three times more common in women than
in men.
Our findings suggest that the sensitivity of TCD is
lower than that reported by AAN Subcommittee
Review of the literature
Assessment, but is similar to the Ôinitial sensitivityÕ
Our review showed that studies of TCD for of 70% of other non-invasive methods for con-
confirming BD do not fulfil the rigorous process firming BD (35). Moreover, specificity of TCD is
required for validation of a diagnostic test (31). very high, close to 100%. A review of TCD studies
Failure to include the whole spectrum of patients confirmed that uniform criteria are urgently needed
because of prerequisites, the fact that the examin- for the use of TCD as a confirmatory test for BD.
ers were not blinded to the diagnosis of BD, the
retrospective design, and an absence of a real
control group were seen in most of these studies.
The mean specificity of the method was 98%, but This work was supported in part by a grant from the Brazilian
some of the false-positive results could probably Federal Government (CAPES) to Dr de Freitas.
have been avoided by examination of the VBA.
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